Targeting homologous recombination deficiency in uterine leiomyosarcoma

by Selleckchem | Sep 25 2023

Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.

Methods: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting.

Results: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs.

Conclusions: Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

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Title: Therapeutic Targeting of Homologous Recombination Deficiency in Uterine Leiomyosarcoma: A Potential Role for PARP Inhibitors

Abstract: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy with a poor prognosis. Mutations in the homologous recombination (HR) DNA repair pathway have been identified in a subset of uLMS cases, highlighting the potential for targeted therapies. This study aimed to screen individuals with uLMS for HR deficiency (HRD) and explore the therapeutic efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) in this context. Additionally, patient-derived xenografts (PDX) were generated for preclinical investigations.

Methods: A cohort of 58 individuals diagnosed with uLMS underwent screening for HRD using whole genome sequencing (WGS), whole exome sequencing (WES), or targeted next-generation sequencing (NGS) panel testing. Clinical outcomes of individuals with HRD uLMS who received PARPi therapy were documented. PDX models were established for further therapeutic investigations.

Results: Analysis of 13 uLMS samples through WGS revealed a predominant COSMIC mutational signature 3, indicative of HRD. Eleven samples exhibited high levels of genome-wide loss of heterozygosity (LOH), while two samples displayed a CHORD score above 50%. One of these samples harbored a homozygous pathogenic alteration in the HR gene BRCA2, while three other samples exhibited homozygous HRD alterations, all involving deletions in BRCA2. In total, 5 out of 58 (9%) individuals with uLMS had HRD. All five individuals gained access to PARPi therapy, and two of three individuals with long-term follow-up achieved a complete response or durable partial response, with the addition of platinum-based chemotherapy upon minor progression during initial PARPi response. Notably, preclinical PDX models demonstrated superior and sustained responses to the PARP1-specific PARPi AZD5305 compared to olaparib alone or olaparib plus cisplatin, even in a PDX derived from a patient who developed PARPi-resistance mutations in PRKDC after PARPi therapy.

Conclusions: Identification of HRD in individuals with uLMS holds therapeutic implications, as PARPi therapy in combination with platinum agents showed promising clinical responses. Furthermore, the use of PARP1-specific PARPi, such as AZD5305, demonstrated favorable outcomes in PDX models. These findings suggest that individuals with HRD uLMS should be considered for inclusion in clinical trials investigating PARP1-specific PARPi as a potential treatment strategy.